Recent Advances in Metal-Organic Frameworks for Applications in Magnetic Resonance Imaging.
Diagnostics is an important part of medical practice. The information required for diagnosis is typically collected by performing diagnostic tests, some of which include imaging. Magnetic resonance imaging (MRI) is one of the most widely used and effective imaging techniques. To improve the sensitivity and specificity of MRI, contrast agents are used. In this review, the usage of metal-organic frameworks (MOFs) and composite materials based on them as contrast agents for MRI is discussed. MOFs are crystalline porous coordination polymers. Due to their huge design variety and high density of metal ions, they have been studied as a highly promising class of materials for developing MRI contrast agents. This review highlights the most important studies and focuses on the progress of the field over the last five years. The materials are classified based on their design and structural properties into three groups: MRI-active MOFs, composite materials based on MOFs, and MRI-active compounds loaded in MOFs. Moreover, an overview of MOF-based materials for heteronuclear MRI including 129Xe and 19F MRI is given.


Zwitterionic Functionalizable Scaffolds with Gyroid Pore Architecture for Tissue Engineering.
Stereolithography-assisted fabrication of hydrogels of carboxybetaine methacrylamide (CBMAA) and a α,ω-methacrylate poly(d,l-lactide-block-ethylene glycol-block- d,l-lactide) (MA-PDLLA-PEG-PDLLA-MA) telechelic triblock macromer is presented. This technique allows printing complex structures with gyroid interconnected porosity possessing extremely high specific area. Hydrogels are characterized by infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), and laser scanning confocal microscopy (LSCM). The copolymerization with zwitterionic comonomer leads hydrogels with high equilibrium water content (EWC), up to 700% while maintaining mechanical robustness. The introduction of carboxybetaine yields excellent resistance to nonspecific protein adsorption while providing a facile way for specific biofunctionalization with a model protein, fluorescein isothiocyanate labeled bovine serum albumin (BSA). The homogeneous protein immobilization across the hydrogel pores prove the accessibility to the innermost pore volumes. The remarkably low protein adsorption combined with the interconnected nature of the porosity allowing fast diffusion of nutrient and waste product and the mimicry of bone trabecular, makes the hydrogels presented here highly attractive for tissue engineering.


Digital imaging scanning system and biomedical applications for biochips.
Biochips have been an advanced technology for biomedical applications since the end of the 20th century. Optical detection systems have been a very important tool in biochip analysis. Microscopes are often inadequate for high resolution and big view-area detection of microarray chips, thus some new optical instruments are required. In this work, a novel digital imaging scanning system with dark-field irradiation is developed for some biomedical applications for microarray chips, characterized by analyzing genes and proteins of clinical samples with high specific, parallel, and nanoliter samples. The novel optical system has a high numerical aperture (NA=0.72), a long working distance (wd>3.0 mm), an excellent contrast and signal-to-noise ratio, a high resolving power close to 3 mum, and an efficiency of collected fluorescence more than two-fold better than that of other commercial confocal biochip scanners. An edge overlap algorithm is proposed for the image restructure of free area detection and correcting scanning position errors to a precision of 1 pixel. A novel algorithm is explored for recognizing the target from the scanning images conveniently, removing noise, and producing the signal matrix of biochip analysis. The digital imaging scanning system is equally as good for the detection of enclosed biochips as it is for the detection of biological samples on a slide surface covered with a glass cover slip or in culture solution. The clinical bacteria identification and serum antibody detection of biochips are described.


Terpenoids of Linaria alpina (L.) Mill. from Dolomites, Italy.
This paper reports the first phytochemical analysis of Linaria alpina (L.) Mill., collected in Dolomites (Italy), a species characteristic of mountain environment. Besides aucubin (4), which is rare in the subgenus Antirrhineae of Plantaginaceae, mainly acidic compounds were found, i.e. oleanolic acid (1), ursolic acid (2) maslinic acid (3) and shikimic acid (5). The pentacyclic triterpenes of L. alpina resulted in relatively high content, whereas flavonoids resulted in low content.


Temperature effects on product-quality-related enzymes in batch CHO cell cultures producing recombinant tPA.
Culture conditions that affect product quality are important to the successful operation and optimization of bioreactors. Previous studies have demonstrated that enzymes, such as proteases and sialidases, accumulate in batch bioreactors. These enzymes are known to be detrimental to the quality of recombinant glycoproteins. Bioreactor temperature has been used to control cell growth and recombinant protein production rates. However, the effect of culture temperature on the production of proteases and sialidases has not been investigated. In this study, Chinese hamster ovary cells were cultured with a temperature profile that decreased from 37 to 34 degrees C over 8 days and with a constant temperature of 37 degrees C. Analysis of extracellular protease activity indicated that two major proteases were present (50 and 69 kDa). The 50 kDa protease activity decreased similarly with time for both culture conditions. The 69 kDa protease activity increased with time for both culture conditions. The constant-temperature cultures had significantly lower 69 kDa protease levels compared to the ramped-temperature cultures in the early stationary phase. Intracellular sialidase activity was present in both cultures. The intracellular sialidase activity increased dramatically for both culture conditions immediately after the cells were inoculated into fresh medium. The initial peak in intracellular sialidase activity was followed by a first-order decay. The intracellular sialidase activities for the two culture conditions were not significantly different. The production of recombinant tissue type plasminogen activator was not significantly different for the two culture conditions. Thus, the previously hypothesized advantages that lower culture temperatures have reduced protease activity and improved productivity do not appear to be universal.


[Joint nursing report of discharge. Quality improvement program for care of post-hospitalized patients].
The author describes the development and practice of program whose purpose is to increase the quality of at home care for post-hospitalized patients and to improve the relationship between Primary Health Care Centers and Specialized Health Care Centers. To this end, a Combined Report for a Certificate of Being Cured has been developed. As this program has been established and developed, its results have improved: More patients who leave the Hospital with a certificate of being cured are registered in Primary Health Care Centers in order to carry out the necessary treatment they require. As time passes, there is a higher degree of identification of the Hospital Service and the Health Center, as well as the Nursing Professional, so that there may be bilateral communication (Hospital/Center to Health-Center to Health/Hospital). Nursing care for this type of patient is becoming quicker all the time especially if we bear in mind the date of the hospital certificate of being cured and the contact date between the patient and the primary Health Center after the patient's release from the hospital.


A Near-Infrared Probe Tracks and Treats Lung Tumor Initiating Cells by Targeting HMOX2.
Tumor initiating cells (TIC) are resistant to conventional anticancer therapy and associated with metastasis and relapse in cancer. Although various TIC markers and their antibodies have been proposed, it is limited to the use of antibodies for in vivo imaging or treatment of TIC. In this study, we discovered heme oxygenase 2 (HMOX2) as a novel biomarker for TIC and developed a selective small molecule probe TiNIR (tumor initiating cell probe with near infrared). TiNIR detects and enriches the functionally active TIC in human lung tumors, and through the photoacoustic property, TiNIR also visualizes lung TIC in the patient-derived xenograft (PDX) model. Furthermore, we demonstrate that TiNIR inhibits tumor growth by blocking the function of HMOX2, resulting in significantly increased survival rates of the cancer model mice. The novel therapeutic target HMOX2 and its fluorescent ligand TiNIR will open a new path for the molecular level of lung TIC diagnosis and treatment.


[A method of measuring centrally determined disturbances of muscle tone (author's transl)].
A technique is described (myotonography) for recording the centrally determined disturbances of muscle tone, whereby the mechanical and electro-myographic changes in the affected muscle groups are accessible to objective and quantitative study. The efficacity and reliability of the method are given and the clinically distinguishable forms of central disturbances of tonus are shown in typical tracings. These are of particular value for assessing the progress of an illness and the results of treatment. In addition it facilitates the interpretation of the patho-physiological processes. The apparatus is so constructed that in the same way as in a clinical examination, a passive extension and flexion of the elbow joint is reproduced over a range of about 100 degrees. In this way it is possible to record the stretch resistance of the extremities as well as the superficial electromyogram of the flexors and extensors.


[Antibodies to DNA stimulates death of mononuclear cells of healthy persons in vitro].
We have shown that polyclonal antibody IgG to native DNA leads to increased levels of apoptosis of moonuclear cells of healthy persons in vitro. Possible biological role of antibodies to DNA is discussed.


Genome-wide association study of growth traits and validation of key mutations (MSTN c.C861T) associated with the muscle mass of meat pigeons.
Selective breeding of meat pigeons is primarily based on growth traits, especially muscle mass (MM). Identification of functional genes and molecular markers of growth and slaughter traits through a genome-wide association study (GWAS) will help to elucidate the underlying molecular mechanisms and provide a theoretical basis for the selective breeding of meat pigeons. The phenotypic data of body weight (BW) and body size (BS) of 556 meat pigeons at 52 and 80 weeks of age were collected. In total, 160 434 high-quality single nucleotide polymorphism sites were obtained by restriction site-associated DNA sequencing. The GWAS analysis revealed that MSTN, IGF2BP3 and NCAPG/LCORL were important candidate genes affecting the growth traits of meat pigeons. IGF2BP3 and NCAPG/LCORL were highly correlated to BW and BS, which are related to overall growth and development, while MSTN was associated with pectoral thickness and BW. Phenotypic association validation with the use of two meat pigeon populations found that the MSTN mutation c.C861T determines the MM. These results provide new insights into the genetic mechanisms underlying phenotypic variations of growth traits and MM in commercial meat pigeons. The identified markers and genes provide a theoretical basis for the selective breeding of meat pigeons.


Canine ehrlichioses: an update.
The development of molecular biology techniques and methods for the isolation and growth of ehrlichias in tissue culture have greatly facilitated the study of these organisms. The available knowledge on ehrlichias is thus rapidly increasing and in this review recent findings on the epidemiology, transmission, clinical and laboratory signs of infection, diagnosis and treatment of canine ehrlichioses are described.


Targeted cellular uptake and siRNA silencing by quantum-dot nanoparticles coated with β-cyclodextrin coupled to amino acids.
Quantum dots (QDs) have the potential to serve as photostable beacons to track siRNA delivery, which is fast becoming an attractive approach to probe gene function in cells. In this paper, we synthesized QD nanoparticles coated with β-cyclodextrin (β-CD) coupled to amino acids with different surface charges (positive, negative, and neutral) through direct ligand-exchange reactions and used them to deliver siRNA. We found that these QDs are diffluent in biological buffer with high colloidal stability and have strong optical emission properties similar to those of tri-n-octylphosphine oxide (TOPO)-coated QDs and also have a long fluorescence lifetime (12.5 ns for L-His-β-CD-coated CdSe/ZnSe QDs). The results of in vitro cytotoxicity and internalization of these modified QDs in normal and cancer cells showed that the β-CD coupled to amino acid outlayers greatly improved the biocompatibility of QDs, and conferred with lower cytotoxicity even at very high concentration. In particular, the L-His-β-CD-coated CdSe/ZnSe QDs presented lower cytotoxicity to these cells (CC(50) value is 180.6±3.4 μg mL(-1) in ECV-304 cells for 48 h). Transmission electron microscope (TEM) images showed that the QDs were localized in vesicles in the cytoplasm of the cells. Furthermore, compared with existing transfection agents, gene-silencing efficiency of the modified QDs was slightly improved for HPV18 E6 gene in HeLa cells by gel electrophoresis analysis. Finally, the unique optical properties of QDs allow visible imaging of siRNA delivery in live cells. Taken together, our study not only provides new insights into the mechanisms of amino acid mediated delivery, but also greatly facilities the monitoring of gene-silencing studies.


How does this make you feel? A comparison of four affect induction procedures.
Affect is a fundamental aspect of the human mind. An increasing number of experiments attempt to examine the influence of affect on other psychological phenomena. To accomplish this research, it is necessary to experimentally modify participants' affective states. In the present experiment, we compared the efficacy of four commonly used affect induction procedures. Participants (38 healthy undergraduate students: 18 males) were randomly assigned to either a pleasant or an unpleasant affect induction group, and then underwent four different affect induction procedures: (1) recall of an affectively salient event accompanied by affectively congruent music, (2) script-driven guided imagery, (3) viewing images while listening to affectively congruent music, and (4) posing affective facial actions, body postures, and vocal expressions. All four affect induction methods were successful in inducing both pleasant and unpleasant affective states. The viewing image with music and recall with music procedures were most effective in enhancing positive affect, whereas the viewing image with music procedure was most effective in enhancing negative affect. Implications for the scientific study of affect are discussed.


Geographic Variance of Cost Associated With Hysterectomy.
To estimate whether the cost of hysterectomy varies by geographic region. This was a cross-sectional, population-based study using the 2013 Healthcare Cost and Utilization Project National Inpatient Sample of women older than 18 years undergoing inpatient hysterectomy for benign conditions. Hospital charges obtained from the National Inpatient Sample database were converted to actual costs using cost-to-charge ratios provided by the Healthcare Cost and Utilization Project. Multivariate regression was used to assess the effects that demographic factors, concomitant procedures, diagnoses, and geographic region have on hysterectomy cost above the median. Women who underwent hysterectomy for benign conditions were identified (N=38,414). The median cost of hysterectomy was $13,981 (interquartile range $9,075-29,770). The mid-Atlantic region had the lowest median cost of $9,661 (interquartile range $6,243-15,335) and the Pacific region had the highest median cost, $22,534 (interquartile range $15,380-33,797). Compared with the mid-Atlantic region, the Pacific (adjusted odds ratio [OR] 10.43, 95% confidence interval [CI] 9.44-11.45), South Atlantic (adjusted OR 5.39, 95% CI 4.95-5.86), and South Central (adjusted OR 2.40, 95% CI 2.21-2.62) regions were associated with the highest probability of costs above the median. All concomitant procedures were associated with an increased cost with the exception of bilateral salpingectomy (adjusted OR 1.03, 95% CI 0.95-1.12). Compared with vaginal hysterectomy, laparoscopic and robotic modes of hysterectomy were associated with higher probabilities of increased costs (adjusted OR 2.86, 95% CI 2.61-3.15 and adjusted OR 5.66, 95% CI 5.11-6.26, respectively). Abdominal hysterectomy was not associated with a statistically significant increase in cost compared with vaginal hysterectomy (adjusted OR 1.01, 95% CI 0.91-1.09). The cost of hysterectomy varies significantly with geographic region after adjusting for confounders.


Limits to sustained energy intake. XXIX. The case of the golden hamster (Mesocricetus auratus).
Golden hamster females have the shortest known gestation period among placental mammals, and at the same time raise very large litters of up to 16 offspring, which are born in a naked and blind state and are only able to pick up food from days 12 to 14 onwards. We quantified energy metabolism and milk production in female golden hamsters raising offspring under cold (8°C), normal (22°C) and hot (30°C) ambient temperature conditions. We monitored energy intake, subcutaneous body temperature, daily energy expenditure, litter size and pup masses over the course of lactation. Our results show that, in line with the concept of heat dissipation limitation, female golden hamsters had the largest energy intake under the coldest conditions and a significantly lower intake at 30°C (partial for influence of ambient temperature: F2,403=5.6; P=0.004). Metabolisable energy intake as well as milk energy output showed the same pattern and were significantly different between the temperatures (partial for milk energy production: F1,40=86.4; P<0.0001), with consistently higher subcutaneous temperatures in the reproductive females (F1,813=36.77; P<0.0001) compared with baseline females. These data suggest that raising offspring in golden hamsters comes at the cost of producing large amounts of body heat up to a level constraining energy intake, similar to that observed in some laboratory mice. Notably, we observed that females seemed to adjust litter size according to their milk production, with the smallest litters (3.4±0.7 pups) being raised by hot-exposed mothers. Future research is needed to unravel the mechanism by which females assess their own milk production capabilities and how this may be linked to litter size at different ambient temperatures. Golden hamsters reach 8-10 times resting metabolic rate when raising offspring under cold conditions, which is compatible with the findings from laboratory mice and other rodents.


hASH1 expression is closely correlated with endocrine phenotype and differentiation extent in pulmonary neuroendocrine tumors.
The human homolog 1 of the Drosophila neurogenic achaete-scute genes, hASH1, is specifically expressed in fetal pulmonary neuroendocrine cells and in some neuroendocrine tumor cell lines. However, no data have been gathered regarding its in vivo expression in tumors. hASH1 mRNA expression was investigated by in situ hybridization in 238 surgically resected lung carcinomas, and the correlations between hASH1 expression status and immunostaining results of neuroendocrine markers chromogranin A, neural cell adhesion molecule, gastrin-releasing peptide and calcitonin, and clinical outcome were analyzed. hASH1 expression was detected in 2/20 (10%) adenocarcinomas, 4/30 (13.3%) typical carcinoids, 11/13 (84.6%) atypical carcinoids, 38/67 (56.7%) large-cell neuroendocrine carcinomas and 56/78 (71.8%) small-cell carcinomas, respectively, but not in any squamous cell carcinoma (0/21) or large-cell carcinoma (0/9). The 2 hASH1+ adenocarcinomas also expressed multiple neuroendocrine markers. Thus, hASH1 expression was restricted to lung cancers with neuroendocrine phenotypes. However, not all neuroendocrine tumors expressed hASH1. Within the entities of large-cell neuroendocrine carcinoma and small-cell carcinoma, hASH1 expression correlated very closely with chromogranin A, gastrin-releasing peptide and calcitonin expression (P<0.0001, r=0.852), but was not related to neural cell adhesion molecule expression (P=0.8892), suggesting that hASH1 expression, at least in lung cancer, is associated with endocrine phenotype expression other than 'neuroendocrine differentiation' in a broad sense. The fact that hASH1 was virtually absent in almost fully differentiated typical carcinoids, but was expressed in most, if not all, less differentiated atypical carcinoids as well as large-cell neuroendocrine carcinomas and small-cell carcinomas, suggests that hASH1 expression in lung cancer imitates its early and transient expression in fetal development, and that hASH1 is instrumental in the establishment, but not in the maintenance, of a cellular endocrine phenotype. Finally, hASH1 expression correlated with a significantly shortened survival in small-cell carcinoma patients (P=0.041).


Genetic professionals' reports of nondisclosure of genetic risk information within families.
Patients attending genetic clinics are often the main gatekeepers of information for other family members. There has been much debate about the circumstances under which professionals may have an obligation, or may be permitted, to pass on personal genetic information about their clients but without their consent to other family members. We report findings from the first prospective study investigating the frequency with which genetics professionals become concerned about the failure of clients to pass on such information to their relatives. In all, 12 UK and two Australian regional genetic services reported such cases over 12 months, including details of actions taken by professionals in response to the clients' failure to disclose information. A total of 65 cases of non-disclosure were reported, representing <1% of the genetic clinic consultations in the collaborating centres during the study period. These included 39 cases of the failure of parents not passing full information to their adult offspring, 22 cases where siblings or other relatives were not given information and four cases where information was withheld from partners -- including former and prospective partners. Professionals reported clients' reasons for withholding information as complex, more often citing concern and the desire to shield relatives from distress rather than poor family relationships. In most cases, the professionals took further steps to persuade their clients to make a disclosure but in no instance did the professional force a disclosure without the client's consent.


Purification and characterization of a human recombinant T-cell protein-tyrosine-phosphatase from a baculovirus expression system.
A 48-kDa human T-cell protein-tyrosine-phosphatase (TC.PTPase) and a truncated form missing an 11-kDa C-terminal segment (TC delta C11.PTPase) were expressed by using the baculovirus system and characterized after extensive purification. The full-length PTPase was restricted to the particulate fraction of the cells from which it could be released by a combination of salt and detergent. The enzyme was entirely specific for phosphotyrosine residues. It displayed a low level of activity toward phosphorylated, reduced, carboxamidomethylated, and maleylated lysozyme (RCML), but was 12 times more active toward phosphorylated myelin basic protein (MBP). By contrast, the 37-kDa form localized in the soluble fraction, and its activity toward RCML was 5 times higher than that observed with MBP. The autophosphorylated cytoplasmic domain of the EGF receptor served as substrate for both enzymes. Limited proteolysis of either protein gave rise to a 33-kDa fragment displaying the substrate specificity of the truncated form. These data lend further support to the view that the C-terminal segment of the T-cell PTPase serves a regulatory function, playing an important role in the localization and substrate specificity of the enzyme.


Effect of Cuff Design on Auscultatory and Oscillometric Blood Pressure Measurements.
Two-piece blood pressure (BP) cuffs are the historical cuff standard. Use of 1-piece cuffs is increasing. Substituting 1-piece for 2-piece cuffs has an unknown effect on measurement accuracy. We compared these cuff types in a 2-phase study using auscultatory and oscillometric techniques. Consenting subjects (aged ≥18 years) with BP levels between 80 and 220mm Hg/50 and 120mm Hg and arm circumferences between 25 and 43cm were studied using the International Standards Organization (ISO) 2013 protocol (modified). A Baum 2-piece cuff was used as the reference standard. A 1-piece Welch Allyn cuff was the comparator. In phase 1 (2-observer auscultation with a mercury sphygmomanometer), 88 subjects were required to obtain 255 paired BP determinations. In phase 2 (oscillometric measurement with a Spacelabs 90207 device), 85 subjects were studied. Each phase was analyzed separately using paired t-tests. Phase 1 mean age was 54.2±20.5 years, mean arm circumference was 29.9±3.7cm, 60% were female, and 32% had hypertension. One-piece cuff mean BPs were lower than the 2-piece cuff means (115.5±15.5/66.4±9.3 vs. 117.8±15.2/67.9±9.2; difference of -2.4±3.6/-1.5±2.4; P values <0.0001 for systolic and diastolic comparisons). Phase 2 mean age was 52.8±20.8 years, mean arm circumference was 29.4±3.9cm, 67% were female, and 38% had hypertension. Mean BPs were lower for the 1-piece compared to the 2-piece cuff (116.5±12.8/67.1±8.1 vs. 120.8±13.5/70.4±8.5; difference of -4.4±3.6/-3.3±2.7; P values <0.0001 for both). Mean BP is lower with 1-piece cuffs vs. 2-piece cuffs. Differences are greater with oscillometry. When performing validation studies and measurements for clinical purposes, cuff type should be taken into account.


A new fixation strategy for addressable nano-network building blocks.
Rapid controlled self-assembly makes DNA ideal for building nanostructures. A problem using hybridized intermediates in hierarchic assembly is their thermodynamic lability. We demonstrate a click-fixation technology by which robust hexagonal DNA modules can be made. This principle is applicable to a wide variety of DNA nanoconstructs.


Prediction of uterine contractions using knowledge-assisted sequential pattern analysis.
The usage of the systemic opioid remifentanil in relieving the labor pain has attracted much attention recently. An optimal dosing regimen for administration of remifentanil during labor relies on anticipating the timing of uterine contractions. These predictions should be made early enough to maximize analgesia efficacy during contractions and minimize the impact of the medication between contractions. We have designed a knowledge-assisted sequential pattern analysis framework to 1) predict the intrauterine pressure in real time; 2) anticipate the next contraction; and 3) develop a sequential association rule mining approach to identify the patterns of the contractions from historical patient tracings (HT).


Geraniol protects against lipopolysaccharide and D-galactosamine-induced fulminant hepatic failure by activating PPARγ.
Geraniol (GOH), a natural component of plant essential oils, exhibits potent antioxidant and anti-inflammatory properties. The aim of this study was to assess the protective effects and mechanisms of GOH on lipopolysaccharide (LPS)/d-galactosamine (D-GalN)-induced fulminant hepatic failure (FHF). Mice were treated with GOH (12.5, 25, and 50 μg/kg) 1 h before challenging LPS (60 mg/kg) and D-GalN (800 mg/kg). 8 h later LPS/D-GlaN treatment, mice were sacrificed and the serum and the liver tissues were collected for testing. The liver pathological changes were assessed by H & E staining. MPO activity, MDA level in liver tissues, and AST, ALT levels in serum were detected by specific detection kits. The levels of TNF-α and IL-1β were detected by ELISA. The expression of NF-κB and PPARγ were detected by western blot analysis and qRT-PCR. The results showed that GOH had a protective effect on LPS/D-GalN-induced FHF, as evidence by the attenuation of liver pathological injury, MPO activity, MDA level, and serum AST and ALT levels. GOH reduced liver TNF-α and IL-1β levels through inhibiting NF-κB signaling pathway activation. Furthermore, GOH increased PPARγ expression in FHF induced by LPS/D-GalN. In conclusion, the present study proved that GOH protects against LPS/D-GalN-induced FHF through inhibiting inflammatory response and increasing PPARγ expression.


Extracorporeal shock waves: perspectives in malignant tumor treatment.
Progress in basic research led to the design of new generations of anticancer drugs with some notable achievements. Over the years, more and more powerful drugs have been developed with the purpose of increasing the rate of response to therapy. As molecular power of chemotherapeutic agents increased, unfortunately also toxicity and undesired side-effects increased. The search for new therapeutic strategies to be used in the management of cancer is one of the more promising strategies to reduce chemotherapy toxicity. Extracorporeal Shock Waves (ESW), widely used for the treatment of urolithiasis, have been reported to cause modifications of cell growth both in vitro and in vivo. They exert an agonist cytotoxic effect with several chemotherapeutic agents, such as cisplatin, doxorubicin, bleomycin, paclitaxel. Moreover, as it has been reported that their main mechanism of action is an increase in cell membrane permeability, ESW are also used to deliver oligonucleotides and other small particles to cells. Recently, it was found that certain dye compounds, in particular porphyrins, can achieve a cytopathogenic effect when the disease site is subjected to ultrasound irradiation. This technique is referred to as sonodynamic therapy. Based on the new knowledge regarding the interaction between ultrasound with bulk liquid, several studies have shown a synergic effect of ESW and porphyrins in vitro, thus opening a new perspective in sonodynamic therapy, able to overcome some drawbacks encountered during conventional anticancer drug treatment. Finally, current advances in bioengineering encouraged the application of nano-scale technologies to medicine. Nanobubbles, composed of an external shell and a gas core, can deliver chemotropic drugs and porfirins, to target tumour tissues in response to physical triggers, and ESW features make them an ideal alternative to ultrasound in combination with drug-loaded nanobubbles in delivery strategies.


Assessment of tissue ingrowth rates in polyurethane scaffolds for tissue engineering.
The continuous development of new biomaterials for tissue engineering and the enhancement of tissue ingrowth into existing scaffolds, using growth factors, create the necessity for developing adequate tools to assess tissue ingrowth rates into porous biomaterials. Current histomorphometric techniques evaluating rates of tissue ingrowth tend either to measure the overall tissue content in an entire sample or to depend on the user to indicate a front of tissue ingrowth. Neither method is particularly suitable for the assessment of tissue ingrowth rates, as these methods either lack the sensitivity required or are problematic when there is a tissue ingrowth gradient rather than an obvious tissue ingrowth front. This study describes a histomorphometric method that requires little observer input, is sensitive, and renders detailed information for the assessment of tissue ingrowth rates into porous biomaterials. This is achieved by examining a number of computer-defined concentric zones, which are based on the distance of a pixel from the scaffold edge. Each zone is automatically analyzed for tissue content, eliminating the need for user definition of a tissue ingrowth front and thus reducing errors and observer dependence. Tissue ingrowth rates in two biodegradable polyurethane scaffolds (Estane and polycaprolactone-polyurethane [PCLPU]) specifically designed for tissue engineering of the knee meniscus were assessed. Samples were subcutaneously implanted in rats with follow-up until 6 months. Especially at the earlier follow-up points, PCLPU scaffolds showed significantly higher tissue ingrowth rates than Estane scaffolds, making the PCLPU scaffold a promising candidate for further studies investigating meniscus tissue engineering.


Do Fruit Ripening Volatiles Enable Resource Specialism in Polyphagous Fruit Flies?
Frugivorous tephritid fruit flies have lineages with high levels of host generalism. These insects use olfaction to locate fruits, but how they are able to recognize the odors of so many different host species is poorly understood. We used a series of behavioral experiments to investigate the role of fruit ripening volatiles as host cues in the Queensland fruit fly, Bactrocera tryoni (Froggatt), a polyphagous pest in Australia. Odors of mature guava (Psidium guajava) attracted female and male flies more strongly than three other ripening stages and guava pulp. We analyzed volatiles from guava odor and selected eleven compounds, all of which elicited an electrophysiological response in the antenna of female flies. Three of these, ethyl acetate, ethyl butyrate, and ethyl propionate, were released at the highest rates from the most attractive ripening stage. In behavioral trials, these three esters were not attractive individually, whereas a combination was necessary and sufficient in attracting female flies. The three-component blend was as attractive as the entire 11-component blend, which without these key volatiles was not attractive. Moreover, injecting low ranking hosts (squash and cucumber) with the three volatiles increased attraction in ovipositing female flies. These fruit flies are classed as generalists, but like many polyphagous insects they could be regarded as resource specialists, preferring specific plant reproductive stages with predictable odor cues. Exploring olfaction from this perspective could improve our understanding of host choice in polyphagous insects, and the selection of volatiles to be used as attractants in insect pest management.


GILT in Thymic Epithelial Cells Facilitates Central CD4 T Cell Tolerance to a Tissue-Restricted, Melanoma-Associated Self-Antigen.
Central tolerance prevents autoimmunity, but also limits T cell responses to potentially immunodominant tumor epitopes with limited expression in healthy tissues. In peripheral APCs, γ-IFN-inducible lysosomal thiol reductase (GILT) is critical for MHC class II-restricted presentation of disulfide bond-containing proteins, including the self-antigen and melanoma Ag tyrosinase-related protein 1 (TRP1). The role of GILT in thymic Ag processing and generation of central tolerance has not been investigated. We found that GILT enhanced the negative selection of TRP1-specific thymocytes in mice. GILT expression was enriched in thymic APCs capable of mediating deletion, namely medullary thymic epithelial cells (mTECs) and dendritic cells, whereas TRP1 expression was restricted solely to mTECs. GILT facilitated MHC class II-restricted presentation of endogenous TRP1 by pooled thymic APCs. Using bone marrow chimeras, GILT expression in thymic epithelial cells (TECs), but not hematopoietic cells, was sufficient for complete deletion of TRP1-specific thymocytes. An increased frequency of TRP1-specific regulatory T (Treg) cells was present in chimeras with increased deletion of TRP1-specific thymocytes. Only chimeras that lacked GILT in both TECs and hematopoietic cells had a high conventional T/Treg cell ratio and were protected from melanoma challenge. Thus, GILT expression in thymic APCs, and mTECs in particular, preferentially facilitates MHC class II-restricted presentation, negative selection, and increased Treg cells, resulting in a diminished antitumor response to a tissue-restricted, melanoma-associated self-antigen.


Racial divergence of a rare laboratory-evolved centromeric fission Cytorace of nasuta-albomicans complex of Drosophila.
Fissioncytorace-1, a member of the nasuta-albomicans complex of Drosophila is an evolutionary product of centric fission, which had occurred in the chromosome X3 of Cytorace 1, a hydridization product of Drosophila nasuta nasuta male (2n=8) and Drosophila nasuta albomicans female (2n=6). Cytorace 1 (males 2n=7; females 2n=6) has inherited this chromosome from its D. n. albomicans parent. The chromosome X3 of D. n. albomicans is a derivative of a centric fusion between the acrocentric chromosome 3 and the chromosome X of D. n. nasuta. The Fissioncytorace-1 has crossed 200 generations from the time of its evolution in the laboratory environment. When this centromeric fission race was subjected to some of the morphophenotypic and fitness assessment to find its overall population fitness showed, increased body size, sternopleural bristle, ovarioles, lifetime fecundity and fertility with reduced interspecific competitive ability and hatching success when compared with its parent (Cytorace 1). These results suggest that the hybrid races must have encountered an early event of recombinational raciation during their evolution in the laboratory environment, which is a unique observation in animal system illustrating the increase in the tempo of evolution after the event of hybridization.


Sarcopenia: current theories and the potential beneficial effect of creatine application strategies.
Sarcopenia, defined as the age-related loss of muscle mass, subsequently has a negative effect on strength, metabolic rate and functionality leading to a reduced quality of life. With the projected increase in life expectancy, the incidence of muscle loss may rise and further drain the health care system, with greater need for hospitalization, treatment, and rehabilitation. Without effective strategies to counteract aging muscle loss, a global health care crisis may be inevitable. Resistance training is well established to increase aging muscle mass and strength. However, muscle and strength loss is still evident in older adults who have maintained resistance training for most of their life, suggesting that other factors such as nutrition may affect aging muscle biology. Supplementing with creatine, a high-energy compound found in red meat and seafood, during resistance training has a beneficial effect on aging muscle. Emerging evidence now suggests that the timing and dosage of creatine supplementation may be important factors for aging muscle accretion. Unfortunately, the long-term effects of different creatine application strategies on aging muscle are relatively unknown.


Effects on accidents of changes in the use of studded tyres in major cities in Norway: a long-term investigation.
This paper reports the findings of two studies made eleven years apart in Norway (Fridstrøm, 2000; Elvik and Kaminska, 2011) to evaluate effects on accidents of changes in the use of studded tyres in major cities in Norway. The first study covered the period from 1991 to 2000, the second study covered the period from 2002 to 2009. In both these periods, large changes in the percentage of cars using studded tyres were found in the cities that were included in the study. There was, in most cities, a tendency for the use of studded tyres to go down. Effects of these changes on injury accidents were evaluated by means of negative binomial regression models, using city and day as the unit of analysis, and including more than twenty explanatory variables in order to control for confounding factors. The effects of changes in the percentage of cars using studded tyres were well described by an accident modification function (dose-response curve), relating the size of changes in the number of accident to the size of the change in the use of studded tyres. Accidents during the season when the use of studded tyres is permitted were found to increase by about 5 percent if the use of studded tyres was reduced by 25 percentage points (e.g. from 50 to 25 percent) and to decline by about 2 percent when the use of studded tyres increased by 20 percentage points.


Widespread employment of conserved C. elegans homeobox genes in neuronal identity specification.
Homeobox genes are prominent regulators of neuronal identity, but the extent to which their function has been probed in animal nervous systems remains limited. In the nematode Caenorhabditis elegans, each individual neuron class is defined by the expression of unique combinations of homeobox genes, prompting the question of whether each neuron class indeed requires a homeobox gene for its proper identity specification. We present here progress in addressing this question by extending previous mutant analysis of homeobox gene family members and describing multiple examples of homeobox gene function in different parts of the C. elegans nervous system. To probe homeobox function, we make use of a number of reporter gene tools, including a novel multicolor reporter transgene, NeuroPAL, which permits simultaneous monitoring of the execution of multiple differentiation programs throughout the entire nervous system. Using these tools, we add to the previous characterization of homeobox gene function by identifying neuronal differentiation defects for 14 homeobox genes in 24 distinct neuron classes that are mostly unrelated by location, function and lineage history. 12 of these 24 neuron classes had no homeobox gene function ascribed to them before, while in the other 12 neuron classes, we extend the combinatorial code of transcription factors required for specifying terminal differentiation programs. Furthermore, we demonstrate that in a particular lineage, homeotic identity transformations occur upon loss of a homeobox gene and we show that these transformations are the result of changes in homeobox codes. Combining the present with past analyses, 113 of the 118 neuron classes of C. elegans are now known to require a homeobox gene for proper execution of terminal differentiation programs. Such broad deployment indicates that homeobox function in neuronal identity specification may be an ancestral feature of animal nervous systems.


Unimolecular photoconversion of multicolor luminescence on hierarchical self-assemblies.
Facile tuning of photophysical properties is highly desirable for boosting the performance and versatility of photoluminescent materials. In an attempt to overcome the challenge of achieving the photoswitching of multicolor luminescence on unimolecular platforms, we here report a novel hierarchical self-assembly of a cyanostilbene-naphthalimide dyad as the realization of phototunable luminescence at the unimolecular level. The work takes advantage of the photoisomerization of the cyanostilbene moiety from the Z form to its E form, which causes a morphological disorder in the molecular self-assembly and gives rise to a dual fluorescent characteristic accompanied by a progressive luminescent color conversion from yellow to green and finally to blue. Such systems with convertible multicolor luminescence might exhibit application potentials for unimolecular selective imaging and labeling, as exemplified by the cell imaging studies presented in this work.


Emlen funnel experiments revisited: methods update for studying compass orientation in songbirds.
Migratory songbirds carry an inherited capacity to migrate several thousand kilometers each year crossing continental landmasses and barriers between distant breeding sites and wintering areas. How individual songbirds manage with extreme precision to find their way is still largely unknown. The functional characteristics of biological compasses used by songbird migrants has mainly been investigated by recording the birds directed migratory activity in circular cages, so-called Emlen funnels. This method is 50 years old and has not received major updates over the past decades. The aim of this work was to compare the results from newly developed digital methods with the established manual methods to evaluate songbird migratory activity and orientation in circular cages.We performed orientation experiments using the European robin (Erithacus rubecula) using modified Emlen funnels equipped with thermal paper and simultaneously recorded the songbird movements from above. We evaluated and compared the results obtained with five different methods. Two methods have been commonly used in songbirds' orientation experiments; the other three methods were developed for this study and were based either on evaluation of the thermal paper using automated image analysis, or on the analysis of videos recorded during the experiment.The methods used to evaluate scratches produced by the claws of birds on the thermal papers presented some differences compared with the video analyses. These differences were caused mainly by differences in scatter, as any movement of the bird along the sloping walls of the funnel was recorded on the thermal paper, whereas video evaluations allowed us to detect single takeoff attempts by the birds and to consider only this behavior in the orientation analyses. Using computer vision, we were also able to identify and separately evaluate different behaviors that were impossible to record by the thermal paper.The traditional Emlen funnel is still the most used method to investigate compass orientation in songbirds under controlled conditions. However, new numerical image analysis techniques provide a much higher level of detail of songbirds' migratory behavior and will provide an increasing number of possibilities to evaluate and quantify specific behaviors as new algorithms will be developed.


Haplotype inference using a Bayesian Hidden Markov model.
Knowledge of haplotypes is useful for understanding block structure in the genome and disease risk associations. Direct measurement of haplotypes in the absence of family data is presently impractical, and hence, several methods have been developed for reconstructing haplotypes from population data. We have developed a new population-based method using a Bayesian Hidden Markov model for the source of the ancestral haplotype segments. In our Bayesian model, a higher order Markov model is used as the prior for ancestral haplotypes, to account for linkage disequilibrium. Our model includes parameters for the genotyping error rate, the mutation rate, and the recombination rate at each position. Computation is done by Markov Chain Monte Carlo using the forward-backward algorithm to efficiently sum over all possible state sequences of the Hidden Markov model. We have used the model to reconstruct the haplotypes of 129 children at a region on chromosome 5 in the data set of Daly et al. [2001] (for which true haplotypes are obtained based on parental genotypes) and of 30 children at selected regions in the CEU and YRI data of the HAPMAP project. The results are quite close to the family-based reconstructions and comparable with the state-of-the-art PHASE program. Our haplotype reconstruction method does not require division of the markers into small blocks of loci. The recombination rates inferred from our model can help to predict haplotype block boundaries, and estimate recombination hotspots.


On the psychology of cooperation in humans and other primates: combining the natural history and experimental evidence of prosociality.
In any given species, cooperation involves prosocial acts that usually return a fitness benefit to the actor. These acts are produced by a set of psychological rules, which will be similar in related species if they have a similar natural history of cooperation. Prosocial acts can be (i) reactive, i.e. in response to specific stimuli, or (ii) proactive, i.e. occur in the absence of such stimuli. We propose that reactive prosocial acts reflect sensitivity to (i) signals or signs of need and (ii) the presence and size of an audience, as modified by (iii) social distance to the partner or partners. We examine the evidence for these elements in humans and other animals, especially non-human primates, based on the natural history of cooperation, quantified in the context of food sharing, and various experimental paradigms. The comparison suggests that humans share with their closest living relatives reactive responses to signals of need, but differ in sensitivity to signs of need and cues of being watched, as well as in the presence of proactive prosociality. We discuss ultimate explanations for these derived features, in particular the adoption of cooperative breeding as well as concern for reputation and costly signalling during human evolution.


Thermoresponsive nanostructured polycarbonate block copolymers as biodegradable therapeutic delivery carriers.
Water-soluble, thermoresponsive block copolymers based on a biodegradable platform were synthesized by the ring opening polymerization of cyclic carbonate monomers functionalized with hydrophilic and hydrophobic groups for application as nanocarriers in medicine. The approach based on cyclic carbonate monomers derived from 2,2-bis(methylol)propionic acid (bis-MPA) allowed a simple and versatile route to functional monomers capable of undergoing ring opening polymerization (ROP). The resulting polymers possessed the predicted molecular weights based on the molar ratio between monomers to initiators and the narrow molecular weight distributions. Transmittance measurement for aqueous polymer solutions provided an evidence for temperature-responsiveness with lower critical solution temperature (LCST) in the range of 36 °C-60 °C, depending on the molecular weight of hydrophilic poly(ethylene glycol) (PEG) chains, compositions of copolymers, molar ratios of hydrophilic to hydrophobic monomers in the corona, and the hydrophobic core. This study showed synthetic advancement toward the design and preparation of biodegradable thermoresponsive polymers with extremely low CMC values for injectable drug delivery systems. TRC350-10,30,60, which possessed an LCST of 36 °C in PBS, was identified as a useful model polymer. Paclitaxel, an anti-cancer drug, was loaded into the micelles efficiently, giving rise to nano-sized particles with a narrow size distribution. Paclitaxel release from the micelles was faster, and cellular uptake of the micelles was higher at the body temperature (i.e. 37 °C) as compared to a temperature below the LCST. While the polymer was not cytotoxic, paclitaxel-loaded micelles killed HepG2 human liver carcinoma cells more efficiently at the body temperature as compared to free paclitaxel and paclitaxel-loaded micelles at the temperature below the LCST. These micelles are ideally suited to deliver anti-cancer drugs to tumor tissues through local injection.


Effect of intraarterial papaverine on cerebral circulation time.
To measure the mean cerebral circulation time (CCT) in patients with symptomatic vasospasm stemming from subarachnoid hemorrhage and to determine any change after papaverine treatment. We studied 27 patients who received intraarterial papaverine from November 1992 to August 1995 to determine the CCT in 59 carotid territories. CCT was measured from the first image in which contrast was seen above the supraclinoid internal carotid artery to the peak filling of parietal cortical veins. Angiograms at the time of presentation were examined in 19 of the 27 patients. A control population of 19 patients (30 carotid territories) was also studied. The mean CCT on presentation was 6.8 seconds +/- 1.1. The prepapaverine mean CCT was 6.1 seconds +/- 1.2. The immediate postpapaverine mean CCT was 3.8 seconds +/- 0.8. CCT decreased in 58 of 59 territories treated with papaverine; the mean change was -35.7%. In eight of these patients, CCT rose on the following day to 6.1 seconds +/- 1.1. In the control group, mean CCT was 5.9 seconds +/- 0.8. The mean CCT in patients with subarachnoid hemorrhage was slightly prolonged on presentation relative to that in control subjects. Intraarterial papaverine produces a consistent decrease in CCT in patients with vasospasm.


Insulin resistance levels predicted metabolic improvement and weight loss after metabolic surgery in Chinese patients with type 2 diabetes.
The causes for failure of metabolic improvement and inadequate weight loss after metabolic surgery (MS) in Chinese patients with type 2 diabetes (T2D) have not been fully elucidated. The effect of insulin resistance (IR) on the outcome of T2D, hypertension, hyperlipidemia, and obesity after MS in Chinese patients with T2D and a body mass index (BMI) of 25-32.5 kg/m2 warrants further study. Patients with T2D and a BMI of 25-32.5 kg/m2 who underwent MS between July 2019 and June 2021 were included. University hospital, China. IR levels were evaluated with the glucose disposal rate (GDR). Improvement of T2D, hypertension, and hyperlipidemia was assessed with the composite triple endpoint (CTEP), and weight loss was assessed with the percent of total weight loss (%TWL). Partial correlation analysis, binary logistic regression analysis, multiple linear regression analysis, receiver operating characteristic curve (ROC) analysis, and subgroup analysis were used to analyze the relationship between the CTEP, %TWL at 1 year postoperative, and GDR preoperative. This study analyzed the data of 51 patients with T2D and a BMI of 25-32.5 kg/m2 (30 men and 21 women) with a mean preoperative GDR of 3.72 ± 1.48 mg/kg/min. Partial correlation coefficients between CTEP, %TWL, and GDR were .303 (P = .041) and .449 (P = .001), respectively. The preoperative GDR was significantly positively correlated with CTEP (OR = 1.610, P = .024) and %TWL (β = 1.38, P = .003). The preoperative GDR predicted cutoff values of 4.36 and 5.35 mg/kg/min for CTEP attainment and %TWL ≥ 20%, respectively. IR levels predicted metabolic improvement and weight loss 1 year after MS in Chinese patients with T2D and a BMI of 25-32.5 kg/m2.


Evidence reversal-when new evidence contradicts current claims: a systematic overview review of definitions and terms.
To explore the terminology and definitions surrounding the phenomenon of evidence reversal (ER)-which occurs when an existing claim is tested and the original evidence is contradicted by new and stronger evidence. For this systematic overview review, multiple medical and gray literature databases were systematically searched from inception to 2016 as well as hand searches of relevant journals, websites, blogs, article bibliographies, citing articles, and related articles. All reviews directly and indirectly defining ER were included and rated for quality using AMSTAR. A total of 87 articles met the inclusion criteria. Fifty unique sets of terms related to ER were identified: nine described the phenomenon of reversal; 17 described the consequences of reversal; 20 described targets; four described potential predictors of reversal. ER has only recently become a topic of formal exploration. There are many terms that relate to the concept of reversal, which fall into the categories of phenomenon, consequences, targets, and potential predictors of reversal. Consensus should be reached on which terms are most appropriate such that subject headings can be developed and cohesion can be brought to this emerging field of meta-research. (PROSPERO Registration number: CRD42014013768).


Postexercise protein intake enhances whole-body and leg protein accretion in humans.
Exercise increases the use of amino acids for glucose production and stimulates the oxidation of amino acids and other substrates to provide ATP for muscular contraction, and thus the availability of amino acids and energy for postexercise muscle protein synthesis may be limiting. The purpose of this study was to determine the potential of postexercise nutrient intake to enhance the recovery of whole-body and skeletal muscle protein homeostasis in humans. Primed-continuous infusions of L-[1-13C]leucine and L-[ring-2H5]phenylalanine were initiated in the antecubital vein and blood was sampled from a femoral vein and a heated (arterialized) hand vein. Each study consisted of a 30-min basal, a 60-min exercise (bicycle at 60% VO2max), and a 180-min recovery period. Five men and five women were studied three times with an oral supplement administered immediately following exercise in random order: NO = 0, 0, 0; SUPP = 0, 8, 3; or SUPP+PRO = 10, 8, 3 g of protein, carbohydrate, and lipid, respectively. Compared to NO, SUPP did not alter leg or whole-body protein homeostasis during the recovery period. In contrast, SUPP+PRO increased plasma essential amino acids 33%, leg fractional extraction of phenylalanine 4-fold, leg uptake of glucose 3.5-fold, and leg and whole-body protein synthesis 6-fold and 15%, respectively. Whereas postexercise intake of either NO or SUPP resulted in a net leg release of essential amino acids and net loss of whole-body and leg protein, SUPP+PRO resulted in a net leg uptake of essential amino acids and net whole-body and leg protein gain. These findings suggest that the availability of amino acids is more important than the availability of energy for postexercise repair and synthesis of muscle proteins.


Study on mechanisms and effect of surfactant-enhanced air sparging.
In an attempt to enhance the effectiveness of air sparging, two sets of experiments were designed to investigate the mechanisms and effect of surfactant-enhanced air sparging (SEAS). The first set was performed at different surface tensions and with different kinds of surfactants (sodium dodecyl benzene sulfonate and Tween-80 [Uniqema Americas LLC, Wilmington, Delaware]), which were added into the contaminated aquifer of different media (particle distribution size = 0.25 to 0.5 mm and 5 to 10 mm). The results indicated that the air saturation in the aquifer increased rapidly at an early stage, then the increase of air saturation slowed down with the increase of airflow rate. The air saturation of medium sand increased with the decrease in water surface tension, and maximum air saturation was achieved at a surface tension of approximately 5 x 10(-2) N/m (50 dyn/cm), which was considered to be the optimum surface tension for air sparging enhancement in the medium sand aquifer. The increase of air saturation in gravel was the result of the increase of foamability and foam stability. The second group of experiments is about the removal of chlorobenzene from the medium sand aquifer. The experiments indicated that chlorobenzene removal by SEAS was more complete and efficient than that of conventional air sparging technology. However, the increase of removal rate and the decrease of lingering concentration by SEAS was not significant, with a further decrease in the surface tension when the surface tension dropped to 5.04 X 10(-2) N/m (50.4 dyn/cm).


Mutations affecting both the rearranged and the unrearranged PML alleles in refractory acute promyelocytic leukaemia.
Acute promyelocytic leukaemia (APL) is characterized by the PML/RARA fusion transcript. PML and RARA mutations have been shown to directly respond to arsenic trioxide (ATO) and all-trans retinoic (ATRA). We analysed the prevalence of PML mutations in 32 patients with de novo or therapy-related APL (t-APL; n = 5), treated with ATO. We identified one ATO-resistant t-APL patient, who presented a PML A216T mutation in both the rearranged and unrearranged PML alleles, and two mutations in the rearranged RARA gene. In this patient, subclones with different PML and RARA mutations acquired clonal dominance during the disease course, probably leading to treatment resistance.


The meningococcal autotransporter AutA is implicated in autoaggregation and biofilm formation.
Autotransporters (ATs) are proteins secreted by Gram-negative bacteria that often play a role in virulence. Eight different ATs have been identified in Neisseria meningitidis, but only six of them have been characterized. AutA is one of the remaining ATs. Its expression remains controversial. Here, we show that the autA gene is present in many neisserial species, but its expression is often disrupted by various genetic features; however, it is expressed in certain strains of N. meningitidis. By sequencing the autA gene in large panels of disease isolates and Western blot analysis, we demonstrated that AutA expression is prone to phase variation at AAGC nucleotide repeats located within the DNA encoding the signal sequence. AutA is not secreted into the extracellular medium, but remains associated with the bacterial cell surface. We further demonstrate that AutA expression induces autoaggregation in a process that, dependent on the particular strain, may require extracellular DNA (eDNA). This property influences the organization of bacterial communities like lattices and biofilms. In vitro assays evidenced that AutA is a self-associating AT that binds DNA. We suggest that AutA-mediated autoaggregation might be particularly important for colonization and persistence of the pathogen in the nasopharynx of the host.


Hyphenated history: Erb-Duchenne brachial plexus palsy.
Throughout history, the discoveries of their predecessors have led physicians to revolutionary advances in the understanding and practice of medicine. The result is a plethora of hyphenated eponyms paying tribute to individuals connected through time by a common interest. The history of Guillaume Duchenne de Boulogne, the "father of electrotherapy and electrodiagnosis," and Wilhelm Heinrich Erb, the "father of neurology," offers insight into the personal and professional lives of these astute clinicians and their collaborative medical breakthrough in the area of neurologic paralysis affecting the upper limbs.


Ultrafine Mn3O4 Nanowires/Three-Dimensional Graphene/Single-Walled Carbon Nanotube Composites: Superior Electrocatalysts for Oxygen Reduction and Enhanced Mg/Air Batteries.
The exploration of highly efficient catalysts for the oxygen reduction reaction to improve sluggish kinetics still remains a great challenge for advanced energy conversion and storage in metal/air batteries. In this work, ultrafine Mn3O4 nanowires/three-dimensional graphene/single-walled carbon nanotube catalysts with an electron transfer number of 3.95 (at 0.60 V vs Ag/AgCl) and kinetic current density of 21.7-28.8 mA cm-2 were developed via a microwave-irradiation-assisted hexadecyl trimethylammonium bromide (CTAB) surfactant procedure to greatly enhance the overall catalytic performance in Mg/air batteries. To match the electrochemical activity of the cathode catalysts, a large-scale Mg anode prepared with micropersimmon-like particles via a mechanical disintegrator and Mg(NO3)2-NaNO2-based electrolyte containing 1.0 wt % trihexyl(tetradecyl)phosphonium chloride ionic liquid were applied. Combining the ultrafine Mn3O4 nanowires/three-dimensional graphene/single-walled carbon nanotube as an efficient electrocatalyst for the oxygen reduction reaction and an Mg micro-/nanoscale anode in the novel electrolyte, the advanced Mg/air batteries demonstrated a high cell open circuit voltage (1.49 V), a high plateau voltage (1.34 V), and a long discharge time (4177 min) at 0.2 mA cm-1, showing a high energy density. Therefore, it is believed that this device configuration has great potential for application in new energy storage technologies.


Combining users' activity survey and simulators to evaluate human activity recognition systems.
Evaluating human activity recognition systems usually implies following expensive and time-consuming methodologies, where experiments with humans are run with the consequent ethical and legal issues. We propose a novel evaluation methodology to overcome the enumerated problems, which is based on surveys for users and a synthetic dataset generator tool. Surveys allow capturing how different users perform activities of daily living, while the synthetic dataset generator is used to create properly labelled activity datasets modelled with the information extracted from surveys. Important aspects, such as sensor noise, varying time lapses and user erratic behaviour, can also be simulated using the tool. The proposed methodology is shown to have very important advantages that allow researchers to carry out their work more efficiently. To evaluate the approach, a synthetic dataset generated following the proposed methodology is compared to a real dataset computing the similarity between sensor occurrence frequencies. It is concluded that the similarity between both datasets is more than significant.


Antigen dose-dependent regulation of B epsilon-memory cell expression.
The data presented in this study document that the phospholipase A2 (PLA2)-specific IgE antibody response in high responder CBA/J mice is solely dependent on the antigen dose used for immunization. Repeated injections of minute doses (MD) of antigen (0.1 microgram/mouse) induce a persisting high level of PLA2-specific IgE antibody titer, whereas large doses (LD) (10 micrograms/mouse) induce a persisting low level of IgE. The IgG antibody titers are the same under both conditions. The low level IgE immune status induced by repeated LD is irreversible and cannot be boosted by MD. In contrast a single LD primes for a secondary IgE response which can be recalled by MD. A high level of PLA2-specific IgE antibodies induced by MD can be downregulated by a single intervening LD of antigen. A low level IgE immune status can be transferred with spleen cells of mice immunized with LD into naive syngeneic recipients, which then fail to mount a high level IgE response upon injection of MD of antigen. The experiments reveal two countercurrent processes, induction of B epsilon-memory cells after a single LD and additional activation of a persisting IgE-specific cellular suppression mechanism after repeated LD of antigen. These properties make the system suitable for the analysis of cellular interactions and of potential desensitization protocols.


Orphanin FQ/nociceptin blocks methamphetamine place preference in rats.
Orphanin FQ/nociceptin (NOC) has been reported to regulate dopaminergic neurotransmission in rewarding pathway, and to suppress the development of conditioned place preference (CPP) induced by certain addictive drugs. In this study, we investigated the effect of NOC on CPP induced by repeated administration of methamphetamine (MAP) in rats. Repeated administration of MAP (1 mg/kg, i.p.) induced substantial CPP. MAP-induced CPP was completely suppressed by NOC (10 nmol, i.c.v.). Pretreatment with [Nphe1]nociceptin(1-13)NH2 (50 nmol, i.c.v.), an antagonist of the NOC receptor, antagonized the suppressive effect of NOC on MAP-induced CPP. These results suggest that NOC blocks MAP-induced CPP by activation of the NOC receptor.


The nuclear actin-related protein ARP6 is a pleiotropic developmental regulator required for the maintenance of FLOWERING LOCUS C expression and repression of flowering in Arabidopsis.
Actin-related proteins (ARPs) are found in the nuclei of all eukaryotic cells, but their functions are generally understood only in the context of their presence in various yeast and animal chromatin-modifying complexes. Arabidopsis thaliana ARP6 is a clear homolog of other eukaryotic ARP6s, including Saccharomyces cerevisiae ARP6, which was identified as a component of the SWR1 chromatin remodeling complex. We examined the subcellular localization, expression patterns, and loss-of-function phenotypes for this protein and found that Arabidopsis ARP6 is localized to the nucleus during interphase but dispersed away from the chromosomes during cell division. ARP6 expression was observed in all vegetative tissues as well as in a subset of reproductive tissues. Null mutations in ARP6 caused numerous defects, including altered development of the leaf, inflorescence, and flower as well as reduced female fertility and early flowering in both long- and short-day photoperiods. The early flowering of arp6 mutants was associated with reduced expression of the central floral repressor gene FLOWERING LOCUS C (FLC) as well as MADS AFFECTING FLOWERING 4 (MAF4) and MAF5. In addition, arp6 mutations suppress the FLC-mediated late flowering of a FRIGIDA-expressing line, indicating that ARP6 is required for the activation of FLC expression to levels that inhibit flowering. These results indicate that ARP6 acts in the nucleus to regulate plant development, and we propose that it does so through modulation of chromatin structure and the control of gene expression.


Renal Cell Carcinoma Surgical Treatment Disparities in American Indian/Alaska Natives and Hispanic Americans in Arizona.
American Indians/Alaska Natives (AI/AN) and Hispanic Americans (HA) have higher kidney cancer incidence and mortality rates compared to non-Hispanic Whites (NHW). Herein, we describe the disparity in renal cell carcinoma (RCC) surgical treatment for AI/AN and HA and the potential association with mortality in Arizona. A total of 5111 stage I RCC cases diagnosed between 2007 and 2016 from the Arizona Cancer Registry were included. Statistical analyses were performed to test the association of race/ethnicity with surgical treatment pattern and overall mortality, adjusting for patients' demographic, healthcare access, and socioeconomic factors. AI/AN were diagnosed 6 years younger than NHW and were more likely to receive radical rather than partial nephrectomy (OR 1.49 95% CI: 1.07-2.07) compared to NHW. Mexican Americans had increased odds of not undergoing surgical treatment (OR 1.66, 95% CI: 1.08-2.53). Analysis showed that not undergoing surgical treatment and undergoing radical nephrectomy were statistically significantly associated with higher overall mortality (HR 1.82 95% CI: 1.21-2.76 and HR 1.59 95% CI: 1.30-1.95 respectively). Mexican Americans, particularly U.S.-born Mexican Americans, had an increased risk for overall mortality and RCC-specific mortality even after adjusting for neighborhood socioeconomic factors and surgical treatment patterns. Although statistically not significant after adjusting for neighborhood-level socioeconomic factors and surgical treatment patterns, AI/AN had an elevated risk of mortality.


Predicting novel trophic interactions in a non-native world.
Humans are altering the global distributional ranges of plants, while their co-evolved herbivores are frequently left behind. Native herbivores often colonise non-native plants, potentially reducing invasion success or causing economic loss to introduced agricultural crops. We developed a predictive model to forecast novel interactions and verified it with a data set containing hundreds of observed novel plant-insect interactions. Using a food network of 900 native European butterfly and moth species and 1944 native plants, we built an herbivore host-use model. By extrapolating host use from the native herbivore-plant food network, we accurately forecasted the observed novel use of 459 non-native plant species by native herbivores. Patterns that governed herbivore host breadth on co-evolved native plants were equally important in determining non-native hosts. Our results make the forecasting of novel herbivore communities feasible in order to better understand the fate and impact of introduced plants.


Intravesical antisense therapy for cystitis using TAT-peptide nucleic acid conjugates.
The present study investigated the potential of intravesical instillation for localized reduction of NGF (nerve growth factor) expression in the urinary bladder. Overexpression of NGF has been linked to the pathogenesis of interstitial cystitis (IC). A minimum free energy algorithm was used to predict suitable regions in mRNA of rat betaNGF, which can be targeted for an antisense approach. The candidate antisense oligos were evaluated for their ability to reduce NGF expression in vitro by cotransfecting HEK293 cells with NGF cDNA. A single oligonucleotide ODN sequence was chosen for testing in an acute cystitis model in rat induced by cyclophosphamide. Overexpression of NGF is known to mediate inflammation of bladder in this model. For improved stability, antisense ODN was replaced with antisense peptide nucleic acid (PNA) and its penetration into bladder was facilitated by tethering TAT peptide sequence. Rat bladders were instilled with either antisense or its scrambled control prior to cystitis induction. Cystometrograms performed on rats under urethane anaesthesia exhibited bladder contraction frequency that was significantly decreased in the antisense treated rats than rats treated with the control. NGF immunoreactivity was also decreased in the urothelium of the antisense treated bladders. Our findings demonstrate the feasibility of using TAT-PNA conjugates for intravesical antisense therapy.


Plasma Exchange Reduces Aβ Levels in Plasma and Decreases Amyloid Plaques in the Brain in a Mouse Model of Alzheimer's Disease.
Alzheimer's disease (AD) is the most common type of dementia, characterized by the abnormal accumulation of protein aggregates in the brain, known as neurofibrillary tangles and amyloid-β (Aβ) plaques. It is believed that an imbalance between cerebral and peripheral pools of Aβ may play a relevant role in the deposition of Aβ aggregates. Therefore, in this study, we aimed to evaluate the effect of the removal of Aβ from blood plasma on the accumulation of amyloid plaques in the brain. We performed monthly plasma exchange with a 5% mouse albumin solution in the APP/PS1 mouse model from 3 to 7 months old. At the endpoint, total Aβ levels were measured in the plasma, and soluble and insoluble brain fractions were analyzed using ELISA. Brains were also analyzed histologically for amyloid plaque burden, plaque size distributions, and gliosis. Our results showed a reduction in the levels of Aβ in the plasma and insoluble brain fractions. Interestingly, histological analysis showed a reduction in thioflavin-S (ThS) and amyloid immunoreactivity in the cortex and hippocampus, accompanied by a change in the size distribution of amyloid plaques, and a reduction in Iba1-positive cells. Our results provide preclinical evidence supporting the relevance of targeting Aβ in the periphery and reinforcing the potential use of plasma exchange as an alternative non-pharmacological strategy for slowing down AD pathogenesis.


Racial Differences in Tobacco Cessation and Treatment Usage After Lung Screening: An Examination of the National Lung Screening Trial.
Black smokers have demonstrated greater lung cancer disease burden and poorer smoking cessation outcomes compared with whites. Lung cancer screening represents a unique opportunity to promote cessation among smokers; however, little is known about the differential impact of screening on smoking behaviors among black and white smokers. Using data from the National Lung Screening Trial (NLST), we examined the racial differences in smoking behaviors after screening. We examined racial differences in smoking behavior and cessation activity among 6,316 white and 497 black (median age, 60 and 59 years, respectively) NLST participants who were current smokers at screening using a follow-up survey on 24-hour and 7-day quit attempts, 6-month continuous abstinence, and the use of smoking cessation programs and aids at 12 months after screening. Using multiple regression analyses, we examined the predictors of 24-hour and 7-day quit attempts and 6-month continuous abstinence. At 12 months after screening, blacks were more likely to report a 24-hour (52.7% vs. 41.2%, p < .0001) or 7-day (33.6% vs. 27.2%, p = .002) quit attempt. However, no significant racial differences were found in 6-month continuous abstinence (5.6% blacks vs. 7.2% whites). In multiple regression, black race was predictive of a higher likelihood of a 24-hour (odds ratio [OR], 1.6, 95% confidence interval [CI], 1.2-2.0) and 7-day (OR, 1.5, 95% CI, 1.1-1.8) quit attempt; however, race was not associated with 6-month continuous abstinence. Only a positive screening result for lung cancer was significantly predictive of successful 6-month continuous abstinence (OR, 2.3, 95% CI, 1.8-2.9). Although blacks were more likely than whites to have 24-hour and 7-day quit attempts, the rates of 6-month continuous abstinence did not differ. Targeted interventions are needed at the time of lung cancer screening to promote abstinence among all smokers. Among smokers undergoing screening for lung cancer, blacks were more likely than whites to have 24-hour and 7-day quit attempts; however, these attempts did not translate to increased rates of 6-month continuous abstinence among black smokers. Targeted interventions are needed at the time of lung cancer screening to convert quit attempts to sustained smoking cessation among all smokers.


A point-of-care diagnostic for differentiating Ebola from endemic febrile diseases.
Hemorrhagic fever outbreaks such as Ebola are difficult to detect and control because of the lack of low-cost, easily deployable diagnostics and because initial clinical symptoms mimic other endemic diseases such as malaria. Current molecular diagnostic methods such as polymerase chain reaction require trained personnel and laboratory infrastructure, hindering diagnostics at the point of need. Although rapid tests such as lateral flow can be broadly deployed, they are typically not well-suited for differentiating among multiple diseases presenting with similar symptoms. Early detection and control of Ebola outbreaks require simple, easy-to-use assays that can detect and differentiate infection with Ebola virus from other more common febrile diseases. Here, we developed and tested an immunoassay technology that uses surface-enhanced Raman scattering (SERS) tags to simultaneously detect antigens from Ebola, Lassa, and malaria within a single blood sample. Results are provided in <30 min for individual or batched samples. Using 190 clinical samples collected from the 2014 West African Ebola outbreak, along with 163 malaria positives and 233 negative controls, we demonstrated Ebola detection with 90.0% sensitivity and 97.9% specificity and malaria detection with 100.0% sensitivity and 99.6% specificity. These results, along with corresponding live virus and nonhuman primate testing of an Ebola, Lassa, and malaria 3-plex assay, indicate the potential of the SERS technology as an important tool for outbreak detection and clinical triage in low-resource settings.


Chromium(VI) induces p53-dependent apoptosis in diploid human lung and mouse dermal fibroblasts.
Some forms of hexavalent chromium [Cr(VI)] are known to cause damage to respiratory-tract tissue and DNA and are thought to be human lung carcinogens. In general, Cr(VI) is mutagenic and carcinogenic at doses that also evoke some cell death, and we previously showed that the predominant mode of death is apoptosis. Because p53 has been shown to initiate apoptosis after genotoxic insults, the objective of these experiments was to determine whether p53 is activated in and necessary for apoptosis of normal diploid human lung fibroblasts (HLF cells) after chromium exposure. By using annexin(V) staining and fluorescent microscopy, we found that Cr(VI) caused up to 14% of HLF cells to undergo apoptosis within 24 h after exposure. In addition, by using western blotting, we found that p53 protein levels increased fourfold to sixfold after exposure to sodium chromate. Because the major function of p53 is as a transcription factor, it must be translocated from the cytoplasm to the nucleus after chromate exposure to be active. Immunofluorescence studies using an antibody against p53 showed that, after chromate exposure, p53 was located in the nucleus of the treated HLF cells. The necessity of p53 for chromium-induced apoptosis was examined in two ways. One approach used dermal fibroblasts from p53 wild-type, heterozygous, and null mice, and the other approach used HLF cells that were transiently transfected with the human papilloma virus E6 gene, which targets p53 for degradation and creates a functional p53-null cell. These studies showed that chromium-induced apoptosis was p53 dependent. Mol. Carcinog. 28:111-118, 2000.


New imaging findings in a patient with central nervous system dysfunction after bone marrow transplantation.
Central nervous system disorders are an important complication of bone marrow transplantation (BMT). We have recently performed cerebral angiography to examine central nervous system dysfunction in a 22-year-old woman with acute lymphoblastic leukaemia who had undergone BMT. Angiography demonstrated multiple stenoses and occlusions in the peripheral branches of the anterior and middle cerebral arteries, a pattern similar to that seen in vasculitis. She was thought to most likely have cytomegalovirus (CMV) vasculitis, but other forms of vasculitis, such as angiitis-like-syndrome-associated graft-versus-host disease could not be excluded. This case suggests that CMV vasculitis may cause central nervous system dysfunction after BMT and that imaging studies may provide useful information about central nervous system disorders in these patients.


Population survival from childhood cancer in Britain during 1978-2005 by eras of entry to clinical trials.
Inclusion in clinical trials is generally viewed as best practice for most newly diagnosed childhood cancers, but the impact on population-based survival has rarely been examined. The population-based data were analysed for 25 853 children (66% of all registered childhood cancers) diagnosed in Britain during 1978-2005 with acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML), Hodgkin lymphoma, non-Hodgkin lymphoma, medulloblastoma, neuroblastoma, Wilms tumour, hepatoblastoma, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma and germ-cell tumours. The Kaplan-Meier survival curves were compared by log-rank tests. Time trends were analysed by Cox regression. Separate analyses were done for children with ALL, medulloblastoma and neuroblastoma according to clinically relevant age thresholds. Survival increased significantly during 1978-2005 for every diagnostic category; the annual reduction in risk of death ranged from 2.7% (rhabdomyosarcoma) to 12.0% (gonadal germ-cell tumours). Survival increased steadily between trial eras for ALL (age 1-14 years) and neuroblastoma (age 1-14 years), but changed little since the mid-1980s for medulloblastoma (age 0-2 years), osteosarcoma or Ewing sarcoma. Changes in survival between trial eras parallel those reported by the relevant clinical trials. The increasing level of participation in trials, facilitated by the organisation of specialist care, has underpinned the substantial improvements in survival seen at the population level.


Menopausal hormone therapy and risk of seropositive rheumatoid arthritis: A nationwide cohort study in Korea.
This retrospective cohort study aimed to investigate the impact of menopausal hormone therapy (MHT) on the incidence of rheumatoid arthritis (RA) in postmenopausal women and to examine the effects of each specific MHT drug. In this Korean population-based cohort study, 452,124 women aged > 40 years who consulted a healthcare provider for menopause were evaluated from January 1, 2011, to December 31, 2014. After propensity score matching, 138,991 pairs were included in the MHT and non-MHT groups. Participants were followed up until December 31, 2020. RA was defined according to the International Classification of Diseases, 10th edition, limited to seropositive RA (M05). RA developed in 567 (0.4 %) of the 138,424 patients in the MHT group. The RA risk in the MHT group was not significantly increased compared with that of controls (hazard ratio [HR] 1.12, 95 % confidence interval [CI] 0.998-1.256). However, MHT use for ≤ 3 years was associated with an increased risk of RA (HR 1.277, 95 % CI 1.127-1.447). When estrogen/progestogen was used, the HR was 1.24 (95 % CI 1.05-1.46), whereas when tibolone was used, the HR was 1.33 (95 % CI 1.13-1.57). The use of MHT did not show a significant impact on the development of RA in postmenopausal women. However, a subanalysis that specifically examined the duration of MHT revealed a noteworthy increase in the risk of RA during the initial 3 years of MHT use.


Longitudinal evaluation of diffusion tensor imaging and cognition in systemic lupus erythematosus.
Objective This pilot study aimed to examine longitudinal changes in brain structure and function in patients with systemic lupus erythematosus (SLE) using diffusion tensor imaging (DTI) and neuropsychological testing. Methods Fifteen female SLE patients with no history of major neuropsychiatric (NP) manifestations had brain magnetic resonance imaging (MRI) with DTI at baseline and approximately 1.5 years later. At the same time points, a standardized battery of cognitive tests yielding a global cognitive impairment index (CII) was administered. At baseline, the SLE patients had mean age of 34.0 years (SD = 11.4), mean education of 14.9 years (SD = 2.1), and mean disease duration of 121.5 months (SD = 106.5). The MRI images were acquired with a 3T GE MRI scanner. A DTI sequence with 33 diffusion directions and b-value of 800 s/mm2 was used. Image acquisition time was about 10 minutes. Results No significant change in cognitive dysfunction (from the CII) was detected. Clinically evaluated MRI scans remained essentially unchanged, with 62% considered normal at both times, and the remainder showing white matter (WM) hyperintensities that remained stable or resolved. DTI showed decreased fractional anisotropy (FA) and increased mean diffusivity (MD) in bilateral cerebral WM and gray matter (GM) with no major change in NP status, medical symptoms, or medications over time. Lower FA was found in the following regions: left and right cerebral WM, and in GM areas including the parahippocampal gyrus, thalamus, precentral gyrus, postcentral gyrus, angular gyrus, parietal lobe, and cerebellum. Greater MD was found in the following regions: left and right cerebral WM, frontal cortex, left cerebral cortex, and the putamen. Conclusions This is the first longitudinal study of DTI and cognition in SLE, and results disclosed changes in both WM and GM without cognitive decline over an 18-month period. DTI abnormalities in our participants were not associated with emergent NP activity, medical decline, or medication changes, and the microstructural changes developed in the absence of macrostructural abnormalities on standard MRI. Microstructural changes may relate to ongoing inflammation, and the stability of cognitive function may be explained by medical treatment, the variability of NP progression in SLE, or the impact of cognitive reserve.


Extranodal Non-Hodgkin's Lymphoma of the Oral Cavity: A Case Report.
Lymphomas are solid malignant tumors having a wide spectrum of clinical and pathological features. Non-Hodgkin's lymphoma (NHL) is a subtype of lymphoma with two-thirds of the cases presenting as lymph node enlargement. The remaining one third of NHL cases has been reported in the extranodal sites, including the gastro intestinal tract, Waldeyer's ring, bone, skin, and brain. Intraoral non-Hodgkin's lymphoma is uncommon and may affect either the jaw bones or occur within the soft tissues of the oral cavity. Here we report a case of non-Hodgkin's lymphoma in a 65-year-old male patient who presented with a growth from the extraction socket. Non-Hodgkin's lymphoma presenting as a growth from the extraction socket is unusual. An orthopantamograph (OPG) was taken which revealed a diffuse radiolucent defect in relation to the extraction socket of the left lower molar region. Routine hemogram, urine analysis, and chest radiograph were normal. Incisional biopsy was performed and the tissue was subjected to histopathological examination. Histopathological and immunohistochemical analysis confirmed the diagnosis of B-cell lymphoma. The patient was referred to a regional cancer institute for further management, where chemotherapy was planned. However, prior to chemotherapy, the patient was diagnosed with brain metastasis and he expired in hospital within one month.


Dietary flaxseed interaction with tamoxifen induced tumor regression in athymic mice with MCF-7 xenografts by downregulating the expression of estrogen related gene products and signal transduction pathways.
Our previous short-term study has shown that 10% flaxseed (FS) inhibits the growth of human estrogen dependent estrogen receptor positive breast tumors (MCF-7) xenografts in ovariectomized (OVX) athymic mice and enhances the tumor inhibitory effect of tamoxifen (TAM). This study determined the long-term effect of 5% and 10% FS, with or without TAM, on the growth of MCF-7 xenografts in athymic mice and the potential mechanisms of actions. OVX mice with established MCF-7 tumors were treated with basal diet (control), 5% FS (5FS), 10% FS (10FS), and TAM (5 mg/pellet, 60-day release), alone or in combination, for 16 wk without estrogen supplementation. Tumor growth was monitored weekly. At sacrifice, the tumors were analyzed by immunohistochemistry for cell proliferation, apoptosis, and expression of estrogen-related genes and signal transduction pathways. Both 5FS and 10FS regressed the pretreatment tumor size by over 90% similar to control. TAM initially regressed the tumors but then induced a regrowth; thus, only a final 6% reduction from pretreatment tumor size was achieved, which was attenuated by combining TAM with 10FS but not with 5FS. TAM combined with 10FS regressed tumors to 55% of pretreatment tumor size due to decreased cell proliferation and increased apoptosis. The expressions of cyclin D1, estrogen receptor alpha, human epidermal growth factor receptor 2, and insulin-like growth factor I receptor in the TAM group were significantly reduced when TAM was combined with 5FS or 10FS. In conclusion, after long-term treatment, FS did not stimulate tumor growth and combined with TAM, regressed tumor size in part due to downregulation of the expression of estrogen-related gene products and signal transduction pathways.


Nuclear hormone receptors as mediators of metabolic adaptability following reproductive perturbations.
Previously, we identified a group of nuclear hormone receptors (NHRs) that promote longevity in the nematode Caenorhabditis elegans following germline-stem cell (GSC) loss. This group included NHR-49, the worm protein that performs functions similar to vertebrate PPARα, a key regulator of lipid metabolism. We showed that NHR-49/PPARα enhances mitochondrial β-oxidation and fatty acid desaturation upon germline removal, and through the coordinated enhancement of these processes allows the animal to retain lipid homeostasis and undergo lifespan extension. NHR-49/PPARα expression is elevated in GSC-ablated animals, in part, by DAF-16/FOXO3A and TCER-1/TCERG1, two other conserved, pro-longevity transcriptional regulators that are essential for germline-less longevity. In exploring the roles of the other pro-longevity NHRs, we discovered that one of them, NHR-71/HNF4, physically interacted with NHR-49/PPARα. NHR-71/HNF4 did not have a broad impact on the expression of β-oxidation and desaturation targets of NHR-49/PPARα. But, both NHR-49/PPARα and NHR-71/HNF4 were essential for the increased expression of DAF-16/FOXO3A- and TCER-1/TCERG1-downstream target genes. In addition, nhr-49 inactivation caused a striking membrane localization of KRI-1, the only known common upstream regulator of DAF-16/FOXO3A and TCER-1/TCERG1, suggesting that it may operate in a positive feedback loop to potentiate the activity of this pathway. These data underscore how selective interactions between NHRs that function as nodes in metabolic networks, confer functional specificity in response to different physiological stimuli.


Genetic polymorphisms in detoxification and DNA repair genes and susceptibility to glycidamide-induced DNA damage.
Acrylamide (AA) is a probable human carcinogen formed in carbohydrate-rich foodstuffs upon heating. Glycidamide (GA), the AA metabolite formed by epoxidation, is considered the ultimate genotoxic agent. In this study, the in vitro genotoxic potential of AA and GA in human whole blood leukocytes was compared using the alkaline comet assay. Although AA did not induce significant DNA damage in the concentrations tested (up to 1000 μM), GA markedly increased the percentage of tail DNA at concentrations ≥250 μM. Further, this study addressed the role of genetic polymorphisms in key genes involved in metabolism and DNA repair pathways (BER, NER, HRR, and NHEJ) on GA-induced genotoxicity assessed by the alkaline comet assay. The results obtained suggested associations between DNA damage and polymorphisms of BER (MUTYH Gln335His and XRCC1 Gln399Arg) and NER (XPC Ala499Val) genes, either alone or in combination.


Loss of the seipin gene perturbs eggshell formation in Caenorhabditiselegans.
Seipin, an evolutionary conserved protein, plays pivotal roles during lipid droplet (LD) biogenesis and is associated with various human diseases with unclear mechanisms. Here, we analyzed Caenorhabditis elegans mutants deleted of the sole SEIPIN gene, seip-1 Homozygous seip-1 mutants displayed penetrant embryonic lethality, which is caused by the disruption of the lipid-rich permeability barrier, the innermost layer of the C. elegans embryonic eggshell. In C. elegans oocytes and embryos, SEIP-1 is associated with LDs and is crucial for controlling LD size and lipid homeostasis. The seip-1 deletion mutants reduced the ratio of polyunsaturated fatty acids (PUFAs) in their embryonic fatty acid pool. Interestingly, dietary supplementation of selected n-6 PUFAs rescued the embryonic lethality and defective permeability barrier. Accordingly, we propose that SEIP-1 may maternally regulate LD biogenesis and lipid homeostasis to orchestrate the formation of the permeability barrier for eggshell synthesis during embryogenesis. A lipodystrophy allele of seip-1 resulted in embryonic lethality as well and could be rescued by PUFA supplementation. These experiments support a great potential for using C. elegans to model SEIPIN-associated human diseases.


Effect of proteins on the synthesis and assembly of calcium phosphate nanomaterials.
Recent developments on biomineralization and biomaterials have demonstrated that proteins play an important role in the formation of biominerals in the body, which induce or inhibit mineralization of calcium phosphate together with modulation of the mineral phase structure. Many efforts have been made to understand the mechanism of this process and mimic the exquisite structure of biominerals in biomimetic methodologies. This review is focused on recent advances in the synthesis of calcium phosphate materials by taking advantage of protein assemblies. We try to review the examples of templates based on proteins and polypeptides that have been successfully employed to manufacture calcium phosphate nanomaterials.


Brucellosis knowledge and preventive practices among herders in Western Mongolia.
Lack of knowledge regarding brucellosis may lead to highly risky practices. Among herders in Mongolia, little research was conducted assessing the extent of knowledge related to brucellosis, the type of preventive behaviours that were practiced, and the relationship between knowledge and behaviour regarding brucellosis. A cross-sectional study was conducted in two provinces of Mongolia where herders were randomly selected to participate in the study. Face-to-face interviews were conducted using a structured questionnaire. In total, 485 herders participated in the study. The results indicated that brucellosis preventive practices were significantly associated with sex, location, use of veterinary services, exposure to TV programs and knowledge of brucellosis. Regional disparities in knowledge and behaviour were observed in this research. Herders were more likely to engage in preventive practices if they had a higher level of knowledge of brucellosis. Findings from this research indicated that the effectiveness of incorporating health education through TV programs, as well as the importance of ensuring access to veterinary services in brucellosis prevention.